Aminocarbonyloxymethyl Ester Prodrugs of Flufenamic Acid and Diclofenac: Suppressing the Rearrangement Pathway in Aqueous Media

Abstract

Aminocarbonyloxymethyl ester prodrugs are known to undergo rearrangement in aqueous solutions to form the corresponding N-acylamine side product via an O-->N intramolecular acyl transfer from the carbamate conjugate base. Novel aminocarbonyloxymethyl esters of diclofenac and flufenamic acid containing amino acid amide carriers were synthesized and evaluated as potential prodrugs displaying less ability to undergo rearrangement. These compounds were prepared in reasonable yield by a four-step synthetic method that uses the appropriate N-Boc-protected amino acid N-hydroxysuccinimide ester and secondary amine and chloromethyl chloroformate as key reactants. Their reactivity in pH 7.4 buffer and 80% human plasma at 37 degrees C was assessed by RP-HPLC. The aminocarbonyloxymethyl esters containing a secondary carbamate group derived from amino acids such as glycine or phenylalanine were hydrolyzed quantitatively to the parent drug both in non-enzymatic and enzymatic conditions, with no rearrangement product being detected. The oral bioavailability in rats was determined for selected diclofenac derivatives. These derivatives displayed a bioavailability of 25 to 68% relative to that of diclofenac, probably due to their poor aqueous solubility and lipophilicity. These results suggest that further optimization of aminocarbonyloxymethyl esters as potential prodrugs for non-steroidal anti-inflammatory drugs require the use of amino acid carriers with ionizable groups to improve aqueous solubility.

Novel Antitumor Platinum(II) Conjugates Containing the Nonsteroidal Anti-inflammatory Agent Diclofenac: Synthesis and Dual Mechanisms of Antiproliferative Effects

“…Notably, various prodrugs derived from NSAIDs containing carboxylic group were prepared in which the carboxylic group was masked, but it has been shown that a major requisite for these prodrugs is that they must be readily hydrolyzed, enzymatically or chemically, to quantitatively release the parent NSAID drug. 54 DCF Ligands Released From cis-[Pt(DCF) 2 (NH 3 ) 2 ] (3) Alter Cell Cycle Profile. To further characterize the cytotoxic effect of 3, an analysis of the cell cycle perturbations was performed in HeLa cells exposed to 3, or to the reference compound cisplatin and free DCF.…”

Evaluation of diclofenac prodrugs for enhancing transdermal delivery

“…Presumably, converting diclofenac to some appropriate prodrugs within the optimal partition coefficient range could achieve higher transdermal penetration. Diclofenac prodrugs have been widely explored, but mostly for the purposes of reducing gastric irritation after oral administration or improving anti-inflammatory efficacy[12-14], with the exception of two studies on diclofenac prodrugs for enhancing transdermal delivery [15, 16]. In those two studies, diclofenac prodrugs were formed by converting diclofenac to diclofenac esters (formed ester with ethylene glycol in one study, and formed esters with different chain length of polyoxyethylene glycols in the other study), and better transdermal permeation was observed.…”

Synthesis, ex Vivo and in Vitro Hydrolysis Study of an Indoline Derivative Designed as an Anti-Inflammatory with Reduced Gastric Ulceration Properties

“…The use of latentiation as a molecular modification strategy provides NSAID produgs with improved safety profiles [ 3 , 4 ]. The prodrug approach afforded compounds with better anti-inflammatory activity, differentiated pharmacokinetic profiles and reduced gastric ulcerogenic activity [ 5 , 6 , 7 , 8 , 9 ]. Using the prodrug approach, one strategy that could be useful is to temporarily mask the carboxylic acid function of the NSAIDs so the prodrug hydrolyzes in vivo to release the active parent NSAID [ 10 , 11 , 12 ].…”